The BRAIN initiative cell census network calls for large-scale, comprehensive approaches to define the compositionofthemammalianbrainatthecellularlevelandusinganoverallstrategythatintegratesmultimodal information (morphology, connectivity, molecules etc..) within a Common Coordinated Framework (CCF) to enable distribution, validation, integration and use of the atlas by the community. The BICCN challenge is enormousandremainsascientificproblemrequiringnewdiscovery,continuousinnovationinmethods, technologiesandpipelineofanalysis.Giventheunparalleledcellulardiversityofthemousebrainandthe needforaninformedcellclassificationscheme,weproposehereanambitiousprojectthataddressesboththe need for scale (coverage of millions of cells) and depth of analysis of each cell and, further, that integrates molecularandanatomicalinformation.Toaddressthischallenge,wehaveassembledacollaborativegroupof keyknowledgeleadersandinnovatorsacrossvariousfieldsofneuroscience,genomics,andtechnology.First, we will apply transformative new droplet scRNA sequencing technologies and next-generation computational methodsanddataprocessingpipelinestocompileawholebraincelltranscriptomeatlasonamassivescale (millionsofsinglecellsandnucleicollectedbrainwide).Thiseffortwillgenerateanunprecedentedinventoryof celltypecompositionanddistributionforthemousebrainwithintheCCF.Second,wewillgenerateaforebrain neuronal atlas that will integrate detailed molecular information (to saturation) of anatomically defined populationswithhigh-resolutionmorphologicalandconnectivityinformationtoprovideanin-depthpictureofa coreportionofthemammalianbrain.Wewillalsogeneratehighlyspecificdriverlinesforprecisemarkingofcell typesandtoenableadaptivemethodsthatrefinecellsamplingtoachievecompleteness.Finally,realizingthe need for innovation in technology to enable work that is made difficult because it requires both scale and precision, we will devote key effort to develop new integrated technological platforms that combine multiple methodstorelateneuronalconnectivitywithtranscriptomesandcellulardistributionatanunprecedentedscale. Our Data Core will integrate, store, and manage multi-modal datasets and provide bioinformatics and computationalexpertise;?andourAdministrativeCore,willcoordinateandoverseeCenter-wideactivities.Our effort is unprecedented for scale and coverage, and it relies on a team of investigators with demonstrated academictrackrecordsofinnovationintechnologyandneurobiology,workinginanenvironmentthatallowsfor implementation of massive pipelines for production workflow. This will guarantee progressive evolution and innovationofmethods,experimentaldesignandanalysistomeetfuturechallengesandsucceedatgenerating acomprehensivemolecularandanatomicalatlasofthemousebrain.
We propose to develop and integrate molecular, anatomic, imaging, and computational technologies and pipelines to build a broad Whole-Brain Cell Transcriptome Atlas that provides an overview of the cell diversityandcompositionwithinthemousebrain,integratedwithahigh-resolutionForebrainNeuronalAtlas that combines comprehensive and in-depth anatomic and molecular characterization of forebrain projection neurons,intoaCommonCoordinateFramework(CCF)-compatiblespatialatlas.
| He, Miao; Huang, Z Josh (2018) Genetic approaches to access cell types in mammalian nervous systems. Curr Opin Neurobiol 50:109-118 |
